The intestine is particularly susceptible to chemoradiation due to a continuous requirement for tissue maintenance by actively cycling intestinal stem cells (ISCs). ISC death is a major side effect of chemoradiotherapy disrupting intestinal homeostasis and causing a loss of intestinal tissue. A major clinical challenge concerns whether a way to drastically reduce this devastating and sometimes lethal intestinal injury caused by intensive chemoradiotherapy during treatment of late-staged cancer with systemic metastasis can be determined. Identification of novel therapeutics that enable ISC survival and function during chemoradiotherapy could greatly increase the range of treatment options, while decreasing catastrophic tissue and organ damage that leads to ultimate death of cancer patients.